PROJECT SUMMARY Several epidemiological studies have found an association between exposure to chemical stressors (such as air pollution) and non-chemical stressors (such as temperature, noise, green space, socioeconomic status [SES], race, and ethnicity), and health outcomes. However, few of these studies have: 1) estimated the health effects across the life course associated with simultaneous exposure to multiple chemical stressors; 2) characterized confounding/effect modification by non-chemical stressors and social determinants of health disparities, particularly factors such as housing conditions and food insecurity; and 3) investigated whether exposure to these chemical stressors can affect health through epigenetic modifications. Moreover, there is a need for new statistical methods that can account for the high dimensionality of the exposures, confounders, and interaction terms in order to understand the effect on health outcomes. We have assembled four unique study populations, three in the Commonwealth of Massachusetts (MA), with data on health outcomes spanning from birth to death, as well as a wealth of information on potential determinants of health disparities. In Aim 1, we will develop innovative statistical methods to estimate health effects associated with a large number of exposures (chemical stressors), while also accounting for large number of potential confounders and interactions. In Aim 2, we will estimate the association between exposure to multiple chemical stressors on birth outcomes, childhood growth rates, and cardiovascular mortality. We will examine effect modification by non-chemical stressors at an individual residence level, including temperatures, noise, green space, and the built environment (neighborhood walkability). We will also examine effect modification by a rich host of individual-level social determinants of health disparities (e.g., age, race/ethnicity, SES). In addition, through the work of Projects 2 and 3, we will have access to housing features that may influence particle infiltration or indoor thermal conditions and measures of environmental health disparities , including housing, neighborhood, material hardship, and sociodemographic stressor constructs. In Aim 3, we will study whether longitudinal changes in epigenetic profiles are associated with air pollution exposures, and how these profiles are modified by determinants of health disparities. The successful completion of this study will address the urgent need for: 1) methods to quantify the health effects of simultaneous exposure to multiple chemical stressors; 2) identifying which non-chemical stressors and social determinants of health disparities exacerbate these effects; 3) identifying disparities in effects; and 4) elucidating potential underlying biological mechanism for environmentally driven health disparities. The knowledge produced upon the successful completion of this project will be essential in mitigating environmentally driven health disparities and improving the health of vulnerable populations and communities.